Testosterone therapy in male sexual function

Male sexual dysfunction is a common occurrence in clinical practice,1 especially in hypogonadal patients, however it is often untreated or undiagnosed.2 This summary is based on a meta-analysis of 41 studies that compared testosterone therapy with placebo or as add-on therapy to phosphodiesterase type 5 inhibitors (PDE5i), and aimed to evaluate the role of testosterone therapy in male sexual function where previous meta-analyses have produced conflicting results.3-5 Based on an extensive search of the Medline, Embase, and Cochrane databases, 1,702 studies were identified and 41 met the criteria for this analysis.

Key Points

This meta-analysis (which included the largest number of studies so far) was performed to more clearly understand the effects of testosterone therapy on male sexual dysfunction, as prior meta-analyses have yielded conflicting results

41 studies were included that compared the effects of testosterone therapy with placebo (29 studies), or testosterone therapy as add-on to PDE5i (12 studies) on male sexual function

Mean follow-up for studies analysing testosterone therapy with placebo was 27 weeks. 5 trials evaluated testosterone therapy in eugonadal patients, 5 in a mixed population of hypogonadal/eugonadal patients, and 19 in hypogonadal patients

Testosterone therapy was not associated with any increase in cardiovascular diseases compared with placebo; whilst hematocrit levels increased, there was no increase in the risk of pathological hematocrit levels compared with placebo

Overall, the lower testosterone levels at baseline, the more pronounced the beneficial effect of TS

Improvements in libido, orgasm and EF had an inverse relationship with baseline T levels

In 894 patients who were treated with testosterone therapy as add-on to PDE5i (mean follow-up of 12 weeks), a positive effect of T was found in non-placebo-controlled trials (effect size 2.96 [95% CI, 1.28–4.64]) but not in placebo-controlled trials

Well-designed studies with large study populations (many of which are industry sponsored) are most likely to produce robust clinical data and are more likely to be published than smaller independent studies

When adjusted for industry-sponsored studies, a positive effect for EF was seen for both sponsored (effect size 1.36 [95% CI, 0.55–2.16]; p=0.001) and non-sponsored (effect size 0.33 [95% CI, 0.13–0.54]; p=0.001) studies, with a larger effect seen in sponsored studies

What is known

T deficiency is a common clinical condition and studies have shown that sexual symptoms, such as erectile dysfunction (ED), are more common in hypogonadal patients.6 The current European Association of Urology (EAU) guidelines recommend the measurement of T in all subjects presenting with ED, adding that any curable cause of ED, including hypogonadism, should be treated first.7 Despite this, the use of testosterone therapy in ED is still controversial.8 Furthermore, the effect of testosterone therapy as an add-on therapy to PDE5i has produced conflicting results. A beneficial effect of testosterone therapy as add-on to PDE5i has been observed in a number of studies;8-10 however, randomised placebo-controlled trials have reported more conflicting results.

Meta-analyses are important tools in evidence-based medicine.11 Using large combined patient populations, they are able to identify and evaluate treatments, however they are associated with some limitations, including publication bias.11 Publication bias occurs as positive and industry-sponsored studies have a greater chance of being published compared with negative and independent studies, which may result in an overestimation of the positive effect of a therapy.12 Previous meta-analyses have shown conflicting results. Jain et al.4 observed a positive effect of testosterone therapy, but only 5 studies were included in this analysis. Additionally, Boloña et al.3 also found a positive effect of testosterone therapy. In contrast, Tsertsvadze et al.5 found no effect on EF of testosterone therapy alone or in testosterone therapy added on to PDE5i.

What this study adds

This meta-analysis provided the most convincing and comprehensive evaluation of testosterone therapy in male sexual function or as add-on to PDE5i so far and included the largest number of studies analysed. Testosterone therapy effectively improved EF and a number of other parameters associated with male sexual function, including libido and orgasmic function. Oral TU was associated with a positive effect on SEF, whereas transdermal and injectable T resulted in significant and similar improvements. However, it should be noted that in patients with a sexual dysfunction related to hypogonadism, testosterone therapy acts as a hormone replacement rather than a treatment for the sexual dysfunction.11

Consistent with findings from previous meta-analyses,13 this analysis noted that testosterone therapy was only associated with improvements in patients with T deficiency at baseline. Our meta-regression analysis showed that improvements in libido, erection, and orgasm were found to have an inverse relationship with testosterone levels at baseline.11 For the first time, this meta-analysis observed an improvement in orgasmic function associated with testosterone therapy. Previous studies have shown that T plays an important role in the regulation of male ejaculation14,15 but this is the first analysis to report that testosterone therapy improves orgasm in hypogonadal patients.

A positive effect of testosterone therapy added to PDE5i was observed but it was not possible to definitively describe the role of testosterone therapy. A positive effect of testosterone therapy was seen in uncontrolled trials, however, this was not noted in placebo controlled trials.

Caution is needed when interpreting results of meta-analyses as they can be subject to publication bias. Following adjustment for publication bias in this meta-analysis, the results remained significant for industry-sponsored trials compared with independent studies. These differences are likely due to trial design, as industry-sponsored studies are generally better designed and enrol larger patient numbers compared with independent studies.

Although the results of this meta-analysis are positive, there was heterogeneity between the studies included so it was not possible to determine a dose-response relationship between testosterone therapy and sexual function. Future studies investigating the ideal testosterone therapy dose for maximum efficacy and tolerability are warranted.